(3,4,7,8,9,10-hexahydro-6, 10 -6H-pyridazino [1,2-a] [1,2,] diazepine-1-carboxylic-acid derivatives

ABSTRACT

A compound of the formula  
                 
 
     wherein R is alkyl or aralkyl of up to 18 carbon atoms, the amine function being optionally protected are used to prepare compounds of the formula  
                 
 
     in which R retains its previous meaning and the amine is optionally protected.

OBJECTS OF THE INVENTION

[0001] It is an object of the invention to provide the novel compoundsof formula I and a process and intermediates for their preparation.

[0002] It is another object of the invention to provide the novelcompounds of formula III and a process for their preparation.

[0003] These and other objects and advantages of the invention willbecome obvious from the following detailed description.

THE INVENTION

[0004] The novel compounds of the invention are compounds of the formula

[0005] wherein R is selected from the group consisting of hydrogen,alkyl of 1 to 18 carbon atoms and aryl and aralkyl of up to 18 carbonatoms and the amine is optionally protected.

[0006] Examples of R as alkyl are methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl and tert-butyl and as aryl or aralkyl are benzyl andnaphthyl.

[0007] Preferred compounds of the invention have the formula

[0008] wherein A is defined as above, R₂ is hydrogen and R₁ is selectedfrom the group consisting of

[0009] R_(a), R_(b), R_(c) and R_(d) are individually selected from thegroup consisting of alkyl of 1 to 18 carbon atoms, aryl and aryl of upto 18 carbon atoms and mono- or polycyclic containing at least oneheteroatom and X is selected from the group consisting of hydrogen,alkyl of 1 to 8 carbon atoms and aryl of up to 14 carbon atoms or R₁ andR₂ together with the nitrogen to which they are attached form a mono- orpolycyclic with at least one heteroatom.

[0010] Examples of cyclic protective groups are

[0011] A preferred compound of formula I has the formula

[0012] wherein R is alkyl of 1 to 8 carbon atoms, especially1,1-dimethylethyl.

[0013] The process of the invention for the preparation of a compound offormula I comprises reacting a compound of the formula

[0014] in racemic form at the 6-member ring and R is as defined andabove the amine is protected with a dehydrogenation agent to form thecorresponding compound of formula I.

[0015] Preferably, the starting material has the formula

[0016] wherein R, R₁ and R₂ have the above definitions and thedehydrogenation agent is a strong base, an oxidizing agent or a sulfuror selenium derivative.

[0017] The compounds of formula II are racemic (SR+SS) at the level ofthe 6-member ring and are novel products. They can be prepared by thefollowing process.

[0018] Product of Preparation a+ Product of Preparation b

[0019] The starting compounds of the said process are described in orcan be prepared as set forth in J. Chem. Soc. Perkins Trans. 1 (1979),Vol. 6, p. 1451-1454 Chem. Soc. Chem. Comm. (1977), p. 635-36.

[0020] The process of the invention for the preparation of a compound ofthe formula

[0021] wherein R is defined as above and the amine is optionallyprotected comprises reacting a compound of formula I with a reducingagent.

[0022] Preferably, the resulting compound has the formula

[0023] wherein R, R₁ and R₂ are defined as above and the reducing agentis hydrogen in the presence of Raney nickel, palladium on carbon,palladium dihydroxide in the presence of talc, ruthenium on carbon orrhodium in the presence of aluminum, more preferably hydrogen in thepresence of Raney nickel. The reaction is effected in the presence of asolvent such as acetic acid, methanol, ethanol, isopropanol,dimethoxyethane, butanone, DMF or acetonitrile.

[0024] The compounds of formula IIIA are intermediates for thepreparation of pharmacological products such as the compounds describedin EP Patent No. 84,095 and in J. Chem. Soc. Perkin Trans. 1, (1986), p.1011. Other products of formula II are useful in a similar process.

[0025] The products of formula II and IIA in the SR form or the form ofa mixture (SR+SS) are novel intermediates as are the compounds offormula III and IIIA with the proviso that R is not hydrogen ortert.-butyl in formula III and in formula IIIA, R is not hydrogen ortert.-butyl when the amine is protected by phthalimido. EP 94,095describes a compound of formula IIIA when R is tert.-butyl and the amineis phthalimido.

[0026] In the following examples, there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

PREPARATION 1 1,1-dimethyl-ethyl9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2-diazepine-1-carboxylate

[0027] Preparation a: 1-(benzyl) and 3-(1,1-dimethyl-ethyl)hexahydro-3-(2H)-pyridazinedicarboxylate

[0028] J. Chem. Soc. Chem. Comm. (1977) p. 635-636 or J. Chem. Soc.Perkin Trans. (1979) Vol 6. p. 1451-1454.

[0029] 920 μl of BF₃-Et₂O and a solution of 18.85 g of terbutyltrichloroacetimidate, 45.5 ml of cyclohexane and 57.5 ml of dichloromethane were introduced at 20° C. into a suspension of 11.50 g of1,2-benzyl hexahydro-1,3(2H) pyridazinedicarboxylate and 115 ml ofdichloromethane. After isolation and purification treatment, theexpected product was obtained.

[0030] Preparation b: benzylγ-(chlorocarbonyl)-1,3-dioxo-1H-isoindole-2(3H)-butanoate

[0031] 30 g of benzyl γ-carboxy-1,3-dioxo-1H-isoindol-(3H) -butanoate(EP 94,095) were introduced, under a nitrogen atmosphere, into 81 ml ofterbutylmethylether. The reaction mixture was then cooled to 0°-2° C.and 17 g of phosphorus pentachloride were added. The reaction mixturewas allowed to return to ambient temperature and was stirred for 6hours, concentrated under reduced pressure, taken to 41° C. and the dryextract obtained was entrained using toluene. The product was held atambient temperature and under a nitrogen atmosphere, then diluted foruse in CH₂Cl₂, to obtain a 0.5 M solution of the desired product.

[0032] Stage A: 1-(benzyl)3-(1,1-dimethylethyl)-2-[1,5-dioxo-2-(1,3-dioxo-14-isoindol-2(3H)-yl-5-benzyloxy-pentyl]-tetrahydro-1,3-(2H)-pyridazinedicarboxylate

[0033] A 0.5 M solution of 52 ml of the product of Preparation b in,methylene chloride was cooled to 0°-1° C. and 5.6 g of the product ofPreparation a and 22 ml of dichloromethane were added thereto. Thereaction mixture was stirred for 3 hours at 0°+1° C. and 1.77 ml ofpyridine and 11 ml of methylene chloride were added. The dichloromethanewas evaporated under reduced pressure at 30° C., followed by taking upin ethyl acetate, washing with aqueous solutions of sodium chloride andsodium bicarbonate. Extraction was carried out with ethyl acetate,followed by drying, rinsing and extracting under reduced pressure toobtain the desired product which was chromatographed on silica andeluting with a heptane-ethyl acetate mixture 60-40 to obtain 4.697 g ofthe desired product melting at ≦35° C.

[0034] Stage B: γ- [[3-[1,1-dimethylethoxy)carbonyl]-tetrahydro-2 (1H)-pyridazinyl]carbonyl]-1,3-dioxo-1H-isoindole-2- (3H) -butanoic acid

[0035] A mixture of 4.61 g of the product of Stage A and 47 ml oftetrahydrofuran was mixed at 20° C. and the reaction mixture washydrogenated at ambient temperature, using 400 mg of palladium on carbonas a catalyst. When the reaction was completed, the reaction mixture wasfiltered and rinsed with THF to obtain 2.76 g of the desired product.

[0036] Stage C: 1,1-dimethylethyl9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino[1,2-a]-1,2-diazepine-1-carboxylate

[0037] A solution of 0.846 ml of thionyl chloride in 2.6 ml ofdichloromethane was added at 0+2° C. to a mixture of 2.6 g of theproduct of Stage B, 26 ml of methylene chloride and 50 μl ofdimethylformamide. The reaction mixture was allowed to return to ambienttemperature and was stirred for 6 hours 20 minutes. The isolation andpurification operations are carried out to obtain the desired product.

Example 1 1,1-dimethylethyl(9S),9-(1,3-dihydro-1,3-dioxopyridazino[1,2-a]-diazepine-1-carboxylate

[0038] a) Preparation of LDA

[0039] 7.2 ml of butyllithium were added at about −60° over 10 minutes,under a nitrogen atmosphere with stirring to a mixture of 20 ml of THFand 3.2 ml of diisoopropylamine. The temperature was allowed to rise to0° C., was held for 1 hour at 0° C. and then was returned to −60° C.

[0040] b) Preparation of C₆H₅SeBr

[0041] 0.26 of bromine were added at 10° C. to a solution of 1.88 g ofdiphenyldiselenium and 6 ml of THF. The reaction mixture was stirred for1 hour at 20° C.

[0042] c) Reaction

[0043] A mixture of 3.44 g of 1,2-dimethylethyl (1S-cis)9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino[1,2-a]-1,2-diazepine-1-carboxylatewas cooled at −65° C. and the solution of LDA prepared above was added.The reaction mixture was stirred for 10 minutes and the solution ofC₆H₅SeBr was added at a temperature of 60°C.±5° C. The temperature wasallowed to return to about 0° C. and 4 ml of water, 1.2 of ml of aceticacid and 4 ml of hydrogen peroxide were added. The temperature was,allowed to rise to 10° C. and the reaction mixture was stirred for 1hour. Then, 40 ml of a 10% aqueous solution of sodium chloride and 80 mlof ethyl acetate were added. The reaction mixture was decanted, washedwith a saturated solution of sodium chloride, and/or sodium bicarbonateat 10%, followed by evaporation under reduced pressure. The resultantmixture was chromatographed on silica, eluting with a methylenechloride-isopropyl ether mixture to obtain 1.3 g of the desired productwith a specific rotation of α_(D)=+126.5° C.=0.335/MeOH

[0044] Use: 1,1-dimethylethyl (1S-cis)9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino[1,2-a] [1,2]-diazepine-1-carboxylate

[0045] a) Preparation of the Catalyst

[0046] A mixture of 0.106 g of Raney nickel (Jansen) and 2 ml of sodiumhydroxide was stirred for 2 hours at 60° C. and the nickel was washedwith water. One drop of acetic acid was added to the last wash water andthe nickel was then washed with ethanol and ethyl acetate. The nickelobtained was kept under reduced pressure.

[0047] b) Reduction

[0048] 3 ml of ethyl acetate were added to 0.053 g of nickel prepared aspreviously and 0.0485 g of the product of Example 1 was added to thesuspension obtained. The hydrogenation stage took place at ambienttemperature, until there was no further absorption of hydrogen. 2 ml ofhydrogen were absorbed and the product had a TLC rf=0.27 eluantisopropyl ether/methylene chloride (50-50).

[0049] Various modifications of the products and processes of theinvention may be made without departing from the spirit or scope thereofand it is to be understood that the invention is intended to be limitedonly as defined in the appended claims.

What we claim is:
 1. A compound of the formula

wherein R is selected from the group consisting of hydrogen, alkyl of 1to 18 carbon atoms and aryl and aralkyl of up to 18 carbon atoms and theamine is free or protected.
 2. A compound of claim 1 of the formula

wherein R is defined as in claim 1 , R₂ is hydrogen and R₁ is selectedfrom the group consisting of

R_(a), R_(b), R_(c) and R_(d) are individually selected from the groupconsisting of alkyl of 1 to 18 carbon atoms, aryl of up to 18 carbonatoms and mono- or polycyclic containing at least one heteroatom and Xis selected from the group consisting of hydrogen, alkyl of 1 to 8carbon atoms and aryl of up to 14 carbon atoms or R₁ and R₂ togetherwith the nitrogen to which they are attached form a mono- or polycyclicwith at least one heteroatom.
 3. A compound of claim 2 wherein R₁ and R₂together with the nitrogen to which they are attached form a polycycliccontaining at least one heteroatom.
 4. A compound of claim 3 of theformula

wherein R is alkyl of 1 to 8 carbon atoms.
 5. A compound of claim 1wherein R is 1,1-dimethyl-ethyl.
 6. A compound of claim 1 which is1,1-dimethylethyl (9S), 9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino[1,2-a]-diazepine-1-carboxylate.7. A process for the preparation of a compound of claim 1 wherein R hasthe definition of claim 1 and the amine is protected comprising reactinga compound of the formula

wherein R has the definition of claim 1 and the amine is protected witha dehydrogenation agent.
 8. The process of claim 7 wherein the startingcompound has the formula

wherein R is defined as in claim 1 , R₂ is hydrogen and R₁ is selectedfrom the group consisting of

R_(a), R_(b), R_(c) and R_(d) are individually selected from the groupconsisting of alkyl of 1 to 18 carbon atoms, aryl of up to 18 carbonatoms and mono- or polycyclic containing at least one heteroatom and Xis selected from the group consisting of hydrogen, alkyl of 1 to 8carbon atoms and aryl of up to 14 carbon atoms or R₁ and R₂ togetherwith the nitrogen to which they are attached form a mono- or polycyclicwith at least one heteroatom.
 9. A process of claim 7 wherein thedehydrogenation agent is selected from the group consisting of a strongbase, an oxidizing agent, a sulfur derivative and a selenium derivative.10. A compound of the formula

wherein R is defined as in claim 1 in SR form or in (SR+SS) mixtureform.
 11. A compound of claim 10 of the formula

wherein R is defined as in claim 1 , R₂ is hydrogen and R₁ is selectedfrom the group consisting of

R_(a), R_(b), R_(c), and R_(d) are individually selected from the groupconsisting of alkyl of 1 to 18 carbon atoms, aryl of up to 18 carbonatoms and mono- or polycyclic containing at least one heteroatom and Xis selected from the group consisting of hydrogen, alkyl of 1 to 8carbon atoms and aryl of up to 14 carbon atoms or R₁ and R₂ togetherwith the nitrogen to which they are attached form a mono- or polycyclicwith at least one heteroatom.
 12. A process for the preparation of acompound of the formula

wherein R is defined as in claim 1 and the amine is optionally protectedcomprising reacting a compound of claim 1 with a reducing agent.
 13. Theprocess of claim 12 wherein the reducing agent is hydrogen in thepresence of Raney nickel.
 14. A process for the preparation of acompound of the formula

wherein R is defined as in claim 1 , R₂ is hydrogen and R₁ is selectedfrom the group consisting of

R_(a), R_(b), R_(c), and R_(d) are individually selected from the groupconsisting of alkyl of 1 to 18 carbon atoms, aryl of up to 18 carbonatoms and mono- or polycyclic containing at least one heteroatom and Xis selected from the group consisting of hydrogen, alkyl of 1 to 8carbon atoms and aryl of up to 14 carbon atoms or R₁ and R₂ togetherwith the nitrogen to which they are attached form a mono- or polycyclicwith at least one heteroatom comprising reacting a compound of claim 2with a reducing agent.
 15. A compound selected from the group consistingof compounds of the formulae

wherein R is defined as in claim 1 , R₂ is hydrogen and R₁ is selectedfrom the group consisting of

R_(a), R_(b), R_(c) and R_(d) are individually selected from the groupconsisting of alkyl of 1 to 18 carbon atoms, aryl of up to 18 carbonatoms and mono- or polycyclic containing at least one heteroatom and Xis selected from the group consisting of hydrogen, alkyl of 1 to 8carbon atoms and aryl of up to 14 carbon atoms of R₁ and R₂ togetherwith the nitrogen to which they are attached form a mono- or polycyclicwith at least one heteroatom with the proviso that R is not hydrogen ortert-butyl and the protected amine is not phthalamido.